1. Field of the Invention
The present invention relates to a compound inhibiting Hsp90 and a pharmaceutical composition comprising the same as an active ingredient.
2. Description of the Related Art
Molecular chaperone such as heat-shock protein families (HSPs) is a protein that can activate nascent proteins and help refolding or decomposing a damaged protein by regulating the folding of a client protein through its activity of changing the ATP dependent structure. A client protein avoids aggregation by binding with such molecular chaperone. This binding can be a help for the intracellular deposition by membrane translocation of the client protein.
It has been known that the molecular chaperone functions of Hsp90, one of the heat-shock protein families, are necessary for the stabilization and activation of various client proteins involved in cell signaling pathway. The amount of Hsp90 takes 1˜2% of the total intracellular proteins in the normal condition in the absence of external stimuli, but it becomes double the amount in the presence of external stimuli. Cancer inducible mutation of a client protein requires stronger and intensive Hsp90 functions, resulting in the over-expression of Hsp90. The over-expressed Hsp90 is commonly found in cancers [Bagatell, R.; Whitesell, L. Altered Hsp90 function in cancer: A unique therapeutic opportunity. Mol. Cancer Ther. 2004, 3, 1021-1030].
The Hsp90 client protein including ErbB2, Src, Met tyrosine kinase, MEK 1/2 (mitogen-activated protein kinase kinase), Akt, Raf-1, cyclin-dependent serine kinases, steroid hormone receptor, telomerase, metalloprotein-2 (MMP-2), and HIF-1α (hypoxia-inducible factor-1α) is found in various signaling pathways involved in cell survival, proliferation, invasion, metastasis, and angiogenesis, etc, and is contributed to the malignant phenotype [Eustace, B. K.; Sakurai, T.; Stewart, J. K.; Yimlamai, D.; Unger, C.; Zehetmeier, C.; Lain, B.; Torella, C.; Henning, S. W.; Beste, G.; Scroggins, B. T.; Neckers, L.; Ilag, L. L.; Jay, D. G. Functional proteomic screens reveal an essential extracellular role for hsp90 alpha in cancer cell invasiveness. Nat. Cell Biol. 2004, 6, 507-514].
In particular, HIF-1α, together with HIF-1β, is a subunit that composes HIF (hydroxia-inducible factor) and induces the expression of VEGF (vascular endothelial growth factor), the oxygen-instable transcriptional factor and one of the angiogenesis-regulating proteins, in order to control angiogenesis in the aspect of vascular destruction and vascular dysfunction. Angiogenesis is a process of generating a new blood vessel, which is necessary for the repair, regeneration, and development of blood vessels or metabolically activated tissues.
However, the pathological angiogenesis not only plays an important role in the growth and expansion of cancer via metastasis but also induces hemorrhage, endoleak, and tissue destruction by abnormally fast angiogenesis. So, the pathological angiogenesis causes not just cancer but also various angiogenesis-dependent diseases including diabetic retinopathy and age-related macular degeneration, and is also involved in chronic infectious diseases including psoriasis and rheumatoid arthritis.
Therefore, the inhibition of Hsp90 is expected to be a efficient treatment method for angiogenesis related diseases and thus the Hsp90 inhibitor can be a potential chemotherapeutic agent for angiogenesis related diseases [Eccles, S.; Massey, A.; Raynaud, F.; Sharp, S.; Box, G.; Valenti, M.; Patterson, L.; de Haven Brandon, A.; Gowan, S.; Boxall, F. NVP-AUY922: a heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis. Cancer Res. 2008, 68, 2850].
Hsp90 exists mainly as a homodimer, which is composed of N-terminal, intermediate region, and C-terminal. Particularly, N-terminal contains adenine nucleotide-binding pocket in which a specific structural motif known as Bergerat fold is included, by which Hsp90 can harbor ATP-binding site, different from other kinases or Hsp70. This structural specificity provides a potential for the development of a selective Hsp90 inhibitor. In fact, followings are the examples of Hsp90 inhibitors so far.

Most of Hsp90 inhibitors, which are exemplified by geldanamycin(2) and its derivative 17-AAG (17-arylamino-17-dimethoxy geldanamycin) having less toxicity, radicicol (3) and the more stable oxime derivative thereof, and the synthetic derivative PU3(4), are known to interact with ATP-binding pocket in N-terminal of Hsp90. In the meantime, the natural antibiotics novobiocin (5), known as a DNA gyrase inhibitor, displays an efficient Hsp90 inhibiting activity by interacting with ATP-binding pocket in C-terminal of Hsp90. Such Hsp90 inhibitors accelerate the degradation of various cancer inducing Hsp90 client proteins, so that they can bring a significant prevention effect in various cancer cell lines of preclinical models. Some of the Hsp90 inhibitors including 17-AAG are in clinical phase.
Deguelin(1) [Clark, E., A relation between rotenone, deguelin and tephrosin. 1931; Vol. 73, pp 17-18.] is a rotenoid compound isolated from Africa origin Mundulea sericea, which is known to have the effect of preventing the development of lung cancer induced by tobacco carcinogens by blocking Akt activation and also to display apoptotic effect and anti-angiogenesis effect in various transformed cell lines and cancer cell lines [Lee, H. Molecular mechanisms of deguelin-induced apoptosis in transformed human bronchial epithelial cells. Biochem. Pharmacol. 2004, 68, 1119-1124].
Even though the potential of deguelin as an anticancer agent or an anti-angiogenesis agent has been confirmed, the toxicity, low solubility, and chemical instability of deguelin draw a limit in its use as a drug.
The present inventors succeeded in synthesizing a compound showing the activity of deguelin but having less toxicity than deguelin and improved physicochemical properties and thereafter confirmed the Hsp90 inhibiting effect, anti-angiogenesis effect, and cytotoxicity of the compound, leading to the completion of this invention.